title: Hypoxic tumor microenvironment in advanced retinoblastoma.
abstract: OBJECTIVE
  Retinoblastoma (RB) is a malignant tumor of infancy and childhood. Unfavorable therapeutic response is still a quest in many tumors, including retinoblastoma. Hypoxic tumor microenvironment is one of the factors that determine the therapeutic response in many tumors. The purpose of this study was to determine the presence of hypoxia and its related proteins; Hypoxia inducible factor-1α (HIF-1α), Carbonic anhydrase IX (CA IX) and survivin in RB and their association with clinicopathological features.
  
  
  METHODS
  We evaluated the expression of HIF-1α and survivin by immunohistochemistry in 42 archival retinoblastoma tumors and CA IX; a hypoxia marker in 33 tumors in the same cohort. The expression was correlated with tumor groups based on invasion, differentiation and IIRC.
  
  
  RESULTS
  Expression of HIF-1α, survivin and CA IX was observed in 83% (35/42), 86% (36/42), and 93% (31/33) of tumors respectively. We observed no significance between HIF-1α and CA IX expression in tumors with invasion, differentiation and in IIRC tumor groups. An increased survivin expression was observed in group E tumors than in group D tumors (P = 0.044). A significant association was observed between HIF-1α and survivin in differentiated (r = -0.582; P = < 0.01) and undifferentiated tumors groups (r = 0.513; P = <0.012). A similar significant association was observed between HIF-1α and CA IX in tumors with high immunoreactivity for HIF-1α (r = 0.833; P = <0.01).
  
  
  CONCLUSIONS
  Based on these observations, we propose that HIF-1α pathway is deregulated in RB. The role of drug resistance and the potential of targeting HIF-1α, CA IX, and survivin in RB should further examined.
authors.affiliation: Department of Ocular Pathology, Vision Research Foundation, Sankara Nethralaya, Chennai, Tamil Nadu, India.
authors.forename: Job
authors.initials: J
authors.lastname: Sudhakar
authors.forename: Nalini
authors.initials: N
authors.lastname: Venkatesan
authors.forename: Shruthi
authors.initials: S
authors.lastname: Lakshmanan
authors.forename: Vikas
authors.initials: V
authors.lastname: Khetan
authors.forename: Subramanian
authors.initials: S
authors.lastname: Krishnakumar
authors.forename: Jyotirmay
authors.initials: J
authors.lastname: Biswas
mesh_terms: D000951:Antigens, Neoplasm / Q000096:biosynthesis* / Q000235:genetics; D014408:Biomarkers, Tumor / Q000096:biosynthesis*; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000096:biosynthesis* / Q000235:genetics; D015687:Cell Hypoxia; D002675:Child, Preschool; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis* / Q000235:genetics; D051034:Inhibitor of Apoptosis Proteins / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D012175:Retinoblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D000077022:Survivin; D059016:Tumor Microenvironment
chemical_list: D000951:Antigens, Neoplasm; C107489:BIRC5 protein, human; D014408:Biomarkers, Tumor; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051034:Inhibitor of Apoptosis Proteins; D009363:Neoplasm Proteins; D000077022:Survivin; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases
keywords: CA IX; HIF-1; chemoresistance; hypoxia; retinoblastoma; survivin